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CD47-SIRP? Interactions Regulate Macrophage Uptake of Plasmodium falciparum-Infected Erythrocytes and Clearance of Malaria In Vivo.

ABSTRACT: CD47 engagement by the macrophage signal regulatory protein alpha (SIRP?) inhibits phagocytic activity and protects red blood cells (RBCs) from erythrophagocytosis. The role of CD47-SIRP? in the innate immune response to Plasmodium falciparum infection is unknown. We hypothesized that disruption of SIRP? signaling may enhance macrophage uptake of malaria parasite-infected RBCs. To test this hypothesis, we examined in vivo clearance in CD47-deficient mice infected with Plasmodium berghei ANKA and in vitro phagocytosis of P. falciparum-infected RBCs by macrophages from SHP-1-deficient (Shp-1(-/-)) mice and NOD.NOR-Idd13.Prkdc(scid) (NS-Idd13) mice, as well as human macrophages, following disruption of CD47-SIRP? interactions with anti-SIRP? antibodies or recombinant SIRP?-Fc fusion protein. Compared to their wild-type counterparts, Cd47(-/-) mice displayed significantly lower parasitemia, decreased endothelial activation, and enhanced survival. Using macrophages from SHP-1-deficient mice or from NS-Idd13 mice, which express a SIRP? variant that does not bind human CD47, we showed that altered SIRP? signaling resulted in enhanced phagocytosis of P. falciparum-infected RBCs. Moreover, disrupting CD47-SIRP? engagement using anti-SIRP? antibodies or SIRP?-Fc fusion protein also increased phagocytosis of P. falciparum-infected RBCs. These results indicate an important role for CD47-SIRP? interactions in innate control of malaria and suggest novel targets for intervention.

SUBMITTER: Ayi K

PROVIDER: S-EPMC4936360 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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CD47-SIRPα Interactions Regulate Macrophage Uptake of Plasmodium falciparum-Infected Erythrocytes and Clearance of Malaria In Vivo.

Ayi Kodjo K Lu Ziyue Z Serghides Lena L Ho Jenny M JM Finney Constance C Wang Jean C Y JCY Liles W Conrad WC Kain Kevin C KC

Infection and immunity 20160623 7

CD47 engagement by the macrophage signal regulatory protein alpha (SIRPα) inhibits phagocytic activity and protects red blood cells (RBCs) from erythrophagocytosis. The role of CD47-SIRPα in the innate immune response to Plasmodium falciparum infection is unknown. We hypothesized that disruption of SIRPα signaling may enhance macrophage uptake of malaria parasite-infected RBCs. To test this hypothesis, we examined in vivo clearance in CD47-deficient mice infected with Plasmodium berghei ANKA and ...[more]

PMID: 27091932

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Project description:BackgroundPrevious comparative proteomic analysis on Plasmodium falciparum isolates of different adhesion properties suggested that protein phosphorylation varies between isolates with different cytoadherence properties. But the extent and dynamic changes in phosphorylation have not been systematically studied. As a baseline for these future studies, this paper examined changes in the phosphoproteome of parasitized red blood cells (pRBC).MethodsMetabolic labelling with [35S] methionine on pRBC and 2D gel electrophoresis (2-DE) has previously been used to show the expression of parasite proteins and changes in protein iso-electric point (PI). 2-DE of different parasite strains was combined with immunoblotting using monoclonal antibodies specifically to phosphorylated serine/threonine and tyrosine, to obtain the phosphorylation profiles throughout the erythrocytic lifecycle. Affinity chromatography was used to purify/enrich phosphorylated proteins and these proteins from mature trophozoite stages which were identified using high-accuracy mass spectrometry and MASCOT search.Results2D-immunoblots showed that P. falciparum infection greatly increased phosphorylation of a set of proteins in pRBC, the dominant size classes for phosphorylated tyrosine proteins were 95, 60, 50 and 30 kDa and for phosphorylated serine/threonine were 120, 95, 60, 50, 43, 40 and 30 kDa. The most abundant molecules from 2D-gel mapping of phosphorylated proteins in ItG infected RBCs were identified by MALDI-TOF. A proteomic overview of phosphorylated proteins in pRBC was achieved by using complementary phosphorylated protein enrichment techniques combined with nano-flow LC/MS/MS analysis and MASCOT MS/MS ions search with phosphorylation as variable modifications. The definite phosphoproteins of pRBC are reported and discussed.ConclusionProtein phosphorylation is a major process in P. falciparum-parasitized erythrocytes. Preliminary screens identified 170 P. falciparum proteins and 77 human proteins as phosphorylated protein in pRBC, while only 48 human proteins were identified in the corresponding fractions from uninfected RBC. Refinement of the search to include significant ion scores indicating a specific phospho-peptide identified 21 P. falciparum proteins and 14 human proteins from pRBC, 13 host proteins were identified from normal RBC. The results achieved by complementary techniques consistently reflect a reliable proteomic overview of pRBC.

Dataset Information

CD47-SIRP? Interactions Regulate Macrophage Uptake of Plasmodium falciparum-Infected Erythrocytes and Clearance of Malaria In Vivo.

Publications

CD47-SIRPα Interactions Regulate Macrophage Uptake of Plasmodium falciparum-Infected Erythrocytes and Clearance of Malaria In Vivo.

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